Many of the efforts to improve on the first generation of CAR-T therapies such that they can reach solid tumors had focused on tweaks inherent to the cancer killing agent — specifically, utilizing more potent T cells as their base, from stem memory T cells to virally associated T cells to marrow infiltrating lymphocytes. But what if just amplifying CAR-T cells can do the job? Darrell Irvine and his team at MIT have some intriguing mouse data for one such tech.
Writing in Science, Irvine — an investigator at the Koch Institute for Integrative Cancer Research — and his postdoc Leyuan Ma describe “amphiphile CAR-T ligands (amph-ligands) that, upon injection, trafficked to lymph nodes and decorated the surfaces of antigen-presenting cells, thereby priming CAR-Ts in the native lymph node microenvironment.” Among mice given the booster shot after CAR-T infusion, 60% experienced a complete response for a variety of tumors including glioblastoma, breast and melanoma. In contrast, barely anything happened to those given just the cell therapy.
It represents a twist to the once-hot — but elusive — cancer vaccine approach, whose premise is to induce an immune attack on tumor cells. It also promises to solve the durability problem of CAR-T that many researchers have highlighted.
“This is a strategy that can be assigned to any CAR-T cell and potentially enhance its function,” he tells me, rendering it exponentially more potent. “So whatever other strategy they might be taking engineering better CARs, building in other genetic payloads into the T cells, this would be a way to make those cells more functional in vivo.”
By sending a vaccine directly to the lymph nodes to stimulate CAR-T cells, he explains, they hit two birds with one stone: Preventing vaccines from getting degraded and CAR-T cells from releasing toxic cytokines — both of which happen in bloodstreams. And it combines the promises of both therapies.
“If we take the animals that appear to be cured and we rechallenge them with tumor cells, they will reject all of them,” Irvine said in an interview with MIT News. “That is another exciting aspect of this strategy. You need to have T cells attacking many different antigens to succeed, because if you have a CAR-T cell that sees only one antigen, then the tumor only has to mutate that one antigen to escape immune attack. If the therapy induces new T-cell priming, this kind of escape mechanism becomes much more difficult.”
To deliver the amph-ligands, the scientists tagged on a lipid tail that binds to albumin in the bloodstream and follows it to the lymph nodes. Once there, the antigen inside the vaccine — either the same one the CAR-T is originally engineered to recognize or another, they tested both — supercharges T cells and spurs their proliferation.
Irvine is hopeful about conducting first-in-human trials within one to two years through Elicio Therapeutics, the second biotech he co-founded. In addition to going after solid tumor indications, he also sees application of his amplified CAR-T in the more traditional CD19 and BCMA settings, as well as deploying the vaccine candidate alone for KRAS-mutant cancers.
Elicio launched earlier this year with $30 million in funding, Robert Connelly (old timers may remember him as founding CEO of Domantis) as chief and Gamida Cells’ Julian Adams as executive chairman. The company is in talks with partners that might bring their own CAR-T to the table.
“Part of the beauty of this is,” he adds, “in the grand scheme of things, it will add nothing to the cost of CAR-T cell therapy because [it’s] essentially a defined molecular entity that can be made at scale pretty simply.”
The research published today was partially funded by J&J — alongside the NIH, the Marble Center for Cancer Nanomedicine and the National Institute of General Medical Sciences. Irvine said the pharma giant is not currently an investor, though it has been in touch.